Substituted p-amino-benzene-sulphonamides and process of producting them



Patented May 10, 1938 UNITED STATES SUBSTITUTED P AMINO BENZENE SUL- PHONAMIDES AND ING THEM PROCESS OF PMDUC- Elmer 11. Stuart, Indianapolis, Ind., minor to Lilly and Company, Indianapolis, Ind., a corporation of- Indiana No Drawing. Application June 26, 1937, Serial No. 150,545

10 Claims.

My invention relates to substituted p-aminobenzene-sulphonamides, particularly p-mandelylaminobenzene-sulphonamide and its intermediate p acetylmandelylamino benzene sulphon- 5 amide, and to the procws of producing them; both end, preferably, I boil a slightly acidified aqueous solution of the p-acetylmandelylamino-benzenesulphonamide for several hours, to remove the acetyl radical. The reaction is apparently as follows:

a H- H H e Q 0 (2) t in s 0=c-cn, +H,oo=c-om (Acetic acid) 0: -NIL O=B'NH! (g-Aoetylmandelylamino (p-Mandelylamino enzone-sulphonamide) benzene-sulphonamide) in their racemic and in their optically active forms. The p-mandelylamino benzene-sulphonamide This new compound, p-mandelylamino-benthus obtained, when recrystallized from alcohol, zene-sulphonamide, in its raoemic form as well as is a white crystalline solid, which melts atabout in its d and 1 forms, on oral administration, has 232 C. corrected. Assay for sulphur indicates excellent protective and curative properties the correctness of the formula given. against various infections, including urinary in- Both my intermediate product and my final fections; and its toxicity is low. The intermediproduct, p acetylmandelylamino benzene solate product, p-acetylmandelylamino-benzenephonamide and p-mandelylamino-benzene-sulsulphonamide, also has therapeutic properties. phon mide r p tive y. are r n y soluble in While variants of my method may be used in water, and more soluble in alcohol; the interpreparing p-mandelylamino benzenesulphonmediate product being soluble in ethyl alcohol to amide, the method I prefer is as follows: the extent of about two parts per hundred, and

p-Arnino-benzene-sulphonamide is treated, in the final product to the extent of slightly less solution or suspension in a non-polar solvent, than one part per hundred. Both can be adminsuch for instance as chloroform or benzene, with istered orally, most conveniently in tablet form, acetylmandelyl chloride (a method for preparing in the treatment of various infections, and are which is described in Organic Syntheses, volume found to be effective.

4, page 1, published 1925 by John Wiley and Sons, The following is an example of the process of Inc., New York); and the whole is then treated manufacturing my new product: to drive ofi the solvent. This produces a reaction To about 70 grams of p-amino-benzene-sulas follows: phonamide are added about 500 cc. of benzene,

H I o H 0 o H t 1 or-tLiz-O o=c-oni o=o-0Hi o= -NH.| 0: -NH,

(p-Amlno- (Acetylmandelyl (p-Acetylmandclylamlnobenzene-sulphonsmldo) chloride) benzene'sulphonamide) The p-acetylmandelylamino-benzene-sulphonto form a suspension; and then there is added amide is a new product, an intermediate in my about 71 grams (about a molecular equivalent or present invention although it also has valuable slightly less) of acetylmandelyl chloride. The properties in combating infections. when first mixture is boiled on a water bath until about half produced this is a light-tan-colored powder, but of the benzene or slightly more than half is on recrystallization from alcohol it is obtained evaporated; and then substantially all the rein the form of white crystals, which melt at maining benzene is re v d y v por ion in 187.5-189.5 0., corrected. vacuo. This leaves a light-tan-colored solid,

In order to obtain my final product, I remove which is the p-acetylmandelylamino-benzeneso the acetyl group in any suitable manner. To this sulphonamide, my intermediate product. If decritical.

sired, this intermediate product may be purified by recrystallization from alcohol; but purification at this stage is not necessary unless it is desired to use this intermediate product as the final product.

To produce the final product, the intermediate product obtained as above, whether or not it has been subjected to recrystallization, has added to it about 1200 cc. of water and about 50 cc. of concentrated (36%) hydrochloric acid. These amounts of water and hydrochloric acid are not The mixture obtained is refluxed for several hours, conveniently about four hours, and then cooled to room temperature. In such refluxing, there is usually at first a considerable foaming, with the particles'cf solid matter largely in and on the foam; but as the refluxing continues the'foam disappears, and the solid particles tend to distribute themselves more or less uniformly through the liquid, which I think is an indication that the reaction has been substantially completed. On cooling, this solid matter tends to settle to the bottom, and may be separated from the liquid by decantation and/or filtration. This solid matter is of a light-tan color as thus first obtained; but on recrystallization from alcohol it is obtained in the form of white crystals. I

Whether my intermediate product and my final product are of the racemic (d1) form, or of the levo form or the dextro form, may be controlled as desired by selecting the initial .acetylmandelyl chloride of the racemic or of the levo or the dextro form; for the form of my intermediate and final products corresponds to the form of that acetylmandelyl chloride in respect of optical rotation. All theseforms of my intermediate product and of my final product are efficacious in the treatment of infections.

1 claim as my invention:

1. The substituted p-amino-benzene sulphonamides, in which a hydrogen atom of the pamino'g'roup is replaced by a radical of the class consisting of the mandelyl and the acetyl-mandelyl groups.

2. The new compound, p-acetylmandelylamino-benzene-sulphonamide, which has the following structural formula:

ieiai no benzei which compound melts at about 1875-1895 C., and is sparingly soluble in water and slightly more soluble in alcohol.

3. The new compound, p-mandelylamino-benzene-sulphonamide, which has the following structural formula:

iii

O: NH:

suiphonamide, and treating. the p-acetylmandel-- to remove the ylamino-benzene-sulphonamide acetyl group therefrom.

.8. The process ofproducing p-mandelylaminobenzehe-sulphcnamiddflhich consists in treating p-acetylmandelylamino-fbenzene-sulphonamide to remove the acetyl group therefrom. V

9. The process ofproducing p-mandelylaminobenzene-sulphonamide, which consists in causing p-amino-benzene-sulphonamide to react with acetylmandelyl chloride in a non-polar solvent to produce p-acetylmandelylamino-benzene-sulphonamide, and boiling the p-acetylmandelylamino-benzene-sulphonamide so obtained in a slightly acidulated aqueous solution to remove the acetyl radical and thus produce the desired pmandelylamino-benzene-sulphonamide.

1G. The process of producing p-mandelylami- -su3phona1nide, which consists in boil- M lylainino-benzene-sulphonamicle in a 51.1 a. 9 fiulated aqueous solution to remove the ace yl radical and thus produce the desired p-mandelylaminoebehzene-sulphonamide.

H. STUART. 

